Healing from Within: How Gut Microbiota Predicts IBD Treatment Success—A Systematic Review

Recent research indicates that the microbiome has a significant impact on the progression of inflammatory bowel disease (IBD) and that creating therapies that change its composition could positively impact the outcomes of IBD treatment. This review summarizes the results of extensive studies that examined IBD patients undergoing several therapies, including anti-TNF medication, vedolizumab, ustekinumab, probiotics, and fecal microbiota transplantation (FMT), and the alterations in their gut microbiota’s composition and function. The objective was to investigate the variety and effectiveness of microbial species in order to discover new biomarkers or therapeutic targets that could improve the outcome of treatment for these patients. This research aimed to offer useful insights into personalized medicine techniques for managing IBD. Beneficial bacteria such as Faecalibacterium prausnitzii and Roseburia have been consistently linked to favorable clinical outcomes, whereas pathogenic bacteria such as Escherichia coli and Clostridioides difficile are associated with worsening disease conditions. Although many studies have examined the role of gut microbiota in IBD, there is still a need for more targeted research on the connection between specific microbial communities and treatment outcomes. This study sought to address this gap by exploring the intricate relationship between the gut microbiota composition and the effectiveness of IBD medications.


Introduction
The intestine is the home for a diverse range of bacteria, viruses, and fungus, together known as the intestinal microbiota, which thrive in this natural environment [1].This microbiota is dependent on the host's gut for survival, has certain metabolic processes, and aids in several physiological functions [2].Furthermore, the gut microbiota significantly influences the host's metabolism, development, and immune system [3].
The two main IBDs, Crohn's disease (CD) and ulcerative colitis (UC), are long-lasting digestive conditions characterized by immune system-related inflammation, the cause of which is still unclear [4,5].Symptoms include diarrhea, abdominal pain, and blood in the stool [6,7].Recent studies suggest that this condition may be linked to an imbalance in intestinal microorganisms or immunomediated factors [8][9][10][11].
Technological advancements, such as metagenomics and meta transcriptomics, have allowed for the identification and validation of the genetic basis of the physiological activities of the gut microbiota [12,13].Despite this significant progress, the cause of IBD remains unknown [14].The increased prevalence in identical twins as opposed to fraternal twins, and within specific families, indicates a genetic factor in the development of the disease [15,16].Furthermore, a group of genome-wide association studies, formally known as GWAS, have discovered a multitude of genetic variants, providing additional evidence for a genetic component of IBD [17,18].Nevertheless, genetics alone is seldom sufficient to initiate the disease [19].The occurrence of IBD has been increasing in parallel with the progress of the modern world, lifestyle changes, and the evolution of society [20].This phenomenon has occurred within a brief timeframe, and its occurrence cannot be solely attributed to genetic alterations or the process of natural selection [21].When examining the causes of these disorders, it is important to examine other variables such as environmental aspects, shifts in dietary patterns from plant-based to animal-based processed meals, the increased prevalence in smoking from a younger age, and antibiotic use [22].
Sir Samuel Wilks, a pioneering physician in the late 19th century, originally proposed the concept that transmissible bacterial pathogens could be the underlying cause of IBD [23].He was also the first to use the phrase "ulcerative colitis" to describe a condition that closely resembles the current understanding of UC [23].
Research has demonstrated that patients with active IBD experience substantial alterations in the composition of their microbiome, such as an increase in the dominant phylotype Proteobacteria and a decrease in Firmicutes [24][25][26][27].These discoveries have caused a fundamental change in the approach to treating this condition, focusing on the goal of restoring the equilibrium of microorganisms in the gut [28,29].Specifically, in IBD, there is a lower variety of microorganisms and an increased presence of dangerous bacteria [30][31][32].Moreover, the literature indicates that altering the gut microbiota through therapies such as prebiotics/probiotics and FMT can have a beneficial effect on the outcomes of IBD [33].This personalized approach not only improves the effectiveness of medications but also reduces side effects, providing a more accurate strategy, focused on the patient, for controlling IBD [34].
Existing reviews often focus on single treatments or limited patient cohorts, failing to provide a holistic view of microbial dynamics across different therapies and populations.Additionally, there is a lack of detailed comparative analyses that incorporate recent advancements in microbiome research and methodologies.This review aimed to bridge this gap by systematically evaluating the impact of diverse treatments on gut microbiota composition, considering both beneficial and harmful bacterial shifts, across a wide range of IBD studies.

Literature Search
A thorough examination of the medical literature published from January 2018 to June 2024 was conducted using the databases PubMed and ScienceDirect.The objective was to document the microbiome composition in Crohn's disease and ulcerative colitis as well as factors that might contribute to the effectiveness of medical treatment, with a focus on biological therapies.

Search Strategy
Boolean operators were used, and they included subject headings and keywords such as "ulcerative colitis", "Crohn's disease", "inflammatory bowel disease", "IBD biological therapies", "IBD mechanism of action", and "gut microbiome."The term "AND" was used to combine different groups of search terms, ensuring comprehensive results.

Study Selection and Rationale for Choices
The study selection process consisted of two stages: Stage 1: Screening of Titles and Abstracts: Initial screening was performed to identify relevant studies based on titles and abstracts.
Stage 2: Full-Text Assessment and Data Extraction: A thorough assessment of the full-text articles was conducted.

Rationale for Methodological Choices
Databases: PubMed and ScienceDirect were chosen for their comprehensive coverage and the high-quality medical literature.
PICO Framework: This framework was chosen to systematically structure the review process, allowing for a clear comparison of different interventions and outcomes [35].
PRISMA Guidelines: Employed to ensure transparency in reporting the systematic review [36].

Resolving Discrepancies in Data Extraction and Study Selection
During Stage 1 (screening titles and abstracts), discrepancies between reviewers were resolved through a consensus approach.Initially, two reviewers independently screened the titles and abstracts of all identified studies.Any discrepancies at this stage were discussed between the two reviewers to reach an agreement.If a consensus could not be reached, a third reviewer was consulted to provide an additional perspective.For Stage 2 (full-text assessment and data extraction), two reviewers independently evaluated each article and extracted relevant data.Any inconsistencies or disagreements in data extraction were again resolved through discussion and consensus between the two reviewers.If necessary, the senior author (Dr.Luana Alexandrescu) was involved to make the final decision (please see Supplementary Materials).

Systematic Review Framework
Population (P): Patients of any age diagnosed with IBD.Intervention (I): Methods of analysis of microbiota.Comparison (C): Gut microbiota of IBD patients before and after the intervention or comparison with healthy controls.
Outcome (O): Establish the relationship between microbiome and IBD and the connection between microbiome and the success of medical treatment.

Focus of the Study
The study focused on the following advanced therapies for IBD: thiopurines, methotrexate, anti-TNF therapy, anti-integrin therapy, ustekinumab, risankizumab, and JAK in-hibitors.Additionally, studies investigating the use of antibiotics, 5-aminosalicylic acid (5ASA) treatment, or corticosteroids were reviewed.

Prisma Framework
A total of 1680 citations were retrieved after scanning the aforementioned databases.After eliminating duplicate entries and excluding 82 items that did not satisfy the search parameters, the list was reduced to 375 remaining articles.
Based on the abstracts, 224 studies were excluded from this research, as they did not meet the criteria.Additionally, 82 papers were eliminated because they did not have the necessary data for extraction and analysis.Furthermore, 20 studies were excluded due to the follow-up period being too short to assess the long-term outcomes.Another 18 studies were omitted because they were commentary or editorial rather than original research.Lastly, 14 articles were disregarded, as the full text was not available.Thus, the final analysis was based on a total of 17 search results that met the criteria for this investigation (Table 1).
Filters applied for PubMed search: Free full text, meta-analysis, randomized controlled trial, systematic review, English, from 1 January 2018-30 June 2024.
The search resulted in a total of 47 citations for "gut microbiota and IBD" available on PubMed and 381 available on ScienceDirect.
The search for "IBD and biological therapies" led to 101 articles on PubMed and 435 articles on ScienceDirect.
The search for "gut microbiome and biological therapies" revealed a total of 195 citations on PubMed and 521 on ScienceDirect.
Following the process of screening and conducting a full-text review, a total of 17 papers were selected for the qualitative analysis (please see Supplementary Materials).The blue dots represent the pooled effect size estimates when each study was excluded from the analysis, while the red lines show the corresponding 95% confidence intervals.The sensitivity analysis demonstrated the strength of the overall findings, as the pooled effect size estimates remained relatively stable across the removal of different studies.Notably, the exclusion of Sokol et al. [40] resulted in a slightly higher pooled effect size (red colour), indicating its influence on the overall estimate.On the other hand, the removal of Crothers et al. [45] (green colour) resulted in a lower pooled effect size.However, the overall consistency, regardless of which study was removed, suggested that the results were not excessively dependent on any single study.
Figure 3 presents a heatmap of the risk of bias analysis across the studies, assessing six categories: selection bias, performance bias, detection bias, attrition bias, reporting bias, and other biases.It identifies areas of potential bias, helping to critically assess the reliability of the findings.The color gradient ranges from blue (low risk) to red (high risk), The blue dots represent the pooled effect size estimates when each study was excluded from the analysis, while the red lines show the corresponding 95% confidence intervals.The sensitivity analysis demonstrated the strength of the overall findings, as the pooled effect size estimates remained relatively stable across the removal of different studies.Notably, the exclusion of Sokol et al. [40] resulted in a slightly higher pooled effect size (red colour), indicating its influence on the overall estimate.On the other hand, the removal of Crothers et al. [45] (green colour) resulted in a lower pooled effect size.However, the overall consistency, regardless of which study was removed, suggested that the results were not excessively dependent on any single study.
Figure 3 presents a heatmap of the risk of bias analysis across the studies, assessing six categories: selection bias, performance bias, detection bias, attrition bias, reporting bias, and other biases.It identifies areas of potential bias, helping to critically assess the reliability of the findings.The color gradient ranges from blue (low risk) to red (high risk), providing a visual representation of the bias levels.Most studies, such as those by Vich Vila et al. [37] and Ananthakrishnan et al. [38], display a low risk of bias across all categories.However, studies such as those by Huang et al. [41] and Pittayanon et al. [49] show higher risks in specific categories, such as selection and performance bias, suggesting areas of potential methodological weakness.The uniform blue seen in many cells points out the general reliability of the findings, while the red and gray areas highlight where caution should be applied when interpreting results.The subplots included in Figure 4 provide a comprehensive overview of the demographic characteristics of the study populations.Thus, Figure 4 includes bar charts, as follows: the top left bar chart reveals a wide range of participant numbers, with Huang et al. [41] using the largest sample size (1120 participants), while Crothers et al. [45] used the smallest sample size (12 participants).This disparity in sample sizes highlights the different scopes and scales of the studies, ranging from extensive reviews to focused pilot studies.
The bar chart on the top right illustrates the gender distribution within these studies.The percentage of male participants varied, with the study by Crothers et al. [45] having the highest male percentage, at 67%, followed closely by the study by Ribaldone et al. [43], at 60%.Most other studies demonstrated a more balanced gender distribution, reflecting The subplots included in Figure 4 provide a comprehensive overview of the demographic characteristics of the study populations.Thus, Figure 4 includes bar charts, as follows: the top left bar chart reveals a wide range of participant numbers, with Huang et al. [41] using the largest sample size (1120 participants), while Crothers et al. [45] used the smallest sample size (12 participants).This disparity in sample sizes highlights the different scopes and scales of the studies, ranging from extensive reviews to focused pilot studies.
participants, showing the mean age and standard deviation for each study.Notably, Ribaldone et al. [43] reported the highest mean age of participants, at 52.5 years, suggesting a focus on an older cohort, whereas Sokol et al. [40] and He et al. [44] targeted slightly younger populations.The inclusion of Rausch et al. [53], with a mean participant age of 42.07 years and a standard deviation of 17.14 for their study, indicated a broad age range within this study, reflecting its diverse participant pool.

Results
These studies presented in Table 1 offer distinct perspectives on the correlation between microbiota and its impact on the efficacy of biological therapy.Table 2 consolidates data to highlight consistent patterns, such as the decrease in beneficial bacteria like Faecalibacterium prausnitzii, Roseburia, Bacteroides, Ruminococcaceae, and Lachnospiraceae in IBD patients, which are important for their anti-inflammatory properties and role in maintaining gut health (Vich Vila et al. [37], Ananthakrishnan et al. [38], Franzosa et al. [39], Olaisen et al. [46], Pittayanon et al. [49]).The bar chart on the top right illustrates the gender distribution within these studies.The percentage of male participants varied, with the study by Crothers et al. [45] having the highest male percentage, at 67%, followed closely by the study by Ribaldone et al. [43], at 60%.Most other studies demonstrated a more balanced gender distribution, reflecting efforts to ensure demographic representation.The addition of the study by Rausch et al. (2023) [53] showed a male percentage of 59%, which aligns with the trend of maintaining gender balance across studies.
The bottom left bar chart shows the female participant percentages, highlighting that most studies maintained a near-equal gender balance, further emphasizing inclusivity.Studies such as those by Fornelos et al. [52], Nikolaus et al. [51], and Forbes et al. [50] achieved a perfect 50/50 gender split, emphasizing the commitment to demographic diversity.
The bottom right scatter plot with error bars describes the age characteristics of participants, showing the mean age and standard deviation for each study.Notably, Ribaldone et al. [43] reported the highest mean age of participants, at 52.5 years, suggesting a focus on an older cohort, whereas Sokol et al. [40] and He et al. [44] targeted slightly younger populations.The inclusion of Rausch et al. [53], with a mean participant age of 42.07 years and a standard deviation of 17.14 for their study, indicated a broad age range within this study, reflecting its diverse participant pool.

Results
These studies presented in Table 1 offer distinct perspectives on the correlation between microbiota and its impact on the efficacy of biological therapy.Table 2 consolidates data to highlight consistent patterns, such as the decrease in beneficial bacteria like Faecalibacterium prausnitzii, Roseburia, Bacteroides, Ruminococcaceae, and Lachnospiraceae in IBD patients, which are important for their anti-inflammatory properties and role in maintaining gut health (Vich Vila et al. [37], Ananthakrishnan et al. [38], Franzosa et al. [39], Olaisen et al. [46], Pittayanon et al. [49]).The table also allows for an easy comparison of findings across studies, emphasizing the increase in harmful bacteria like Escherichia coli, Clostridioides difficile, Enterobacteriaceae, and Proteobacteria.According to studies conducted by Vich Vila et al. [37], Franzosa et al. [39], and Coufal et al. [48], this shift towards dysbiosis exacerbates inflammation and disease severity.The presence of these bacteria correlates with increased disease activity and highlights their role in driving intestinal inflammation.
The table also groups studies examining the impact of FMT and other therapeutic interventions on gut microbiota.FMT responders showed an increase in beneficial bacteria such as Faecalibacterium prausnitzii, Roseburia spp., and Ruminococcus spp., which are linked to positive clinical outcomes and remission maintenance in IBD patients (Sokol et al. [40], Costello et al. [42], Crothers et al. [45]).Notably, Ribaldone et al. [43] highlighted that Faecalibacterium prausnitzii, Ruminococcus gnavus, Escherichia coli, and Bacteroides ovatus decreased in FMT responders, emphasizing the complex dynamics of gut microbiota in response to therapy.
Table 3 details the specific therapies used in various studies, the key bacteria that were increased or decreased, and additional notes on study populations and methodologies.This table is essential as it outlines the microbiota changes linked to specific treatments like anti-TNF therapy, vedolizumab, ustekinumab, and FMT, providing a nuanced understanding of how different therapies impact gut microbiota.Significant increases were noted in Faecalibacterium prausnitzii, Roseburia, and other members of the Ruminococcaceae family across several studies [37,40,43] especially following treatments such as anti-TNF therapy, FMT, and probiotics.For instance, Sokol et al. [40] and Costello et al. [42] found that FMT led to an increase in Faecalibacterium prausnitzii and Roseburia, which are linked to positive clinical outcomes and remission maintenance in IBD patients.
Probiotic treatments have also led to increased levels in Lactobacillus and Bifidobacterium species.Huang et al. [41] demonstrated that various probiotic strains could modulate gut microbiota, reduce inflammation, and improve intestinal barrier function, further supporting their therapeutic potential in managing IBD.On the other hand, pathogenic bacteria, including Escherichia coli, Clostridioides difficile, and other Proteobacteria, are regularly decreased after successful treatments [40,44].
Ribaldone et al. [43] also observed a decrease in Proteobacteria in CD patients treated with adalimumab, indicating a positive shift towards a healthier gut microbiota composition.Similarly, Rausch et al. [53] reported that successful FMT led to a decrease in harmful bacteria such as Escherichia coli and Clostridioides difficile, further emphasizing the therapeutic potential of microbiota modulation in IBD management.
The data across multiple studies reinforce the importance of gut microbiota as both a marker and mediator of health in IBD, suggesting that future treatments should continue to focus on microbiota modulation to achieve better patient outcomes [37,[40][41][42]44,53].
Figure 5 summarizes the impact of various therapies on gut microbiota composition.It visually demonstrates the contrasting changes in important bacteria, providing a quick reference for understanding which therapies promote beneficial bacteria and which reduce harmful bacteria.[53] reported that successful FMT led to a decrease in harmful bacteria such as Escherichia coli and Clostridioides difficile, further emphasizing the therapeutic potential of microbiota modulation in IBD management.
The data across multiple studies reinforce the importance of gut microbiota as both a marker and mediator of health in IBD, suggesting that future treatments should continue to focus on microbiota modulation to achieve better patient outcomes [37,[40][41][42]44,53].
Figure 5 summarizes the impact of various therapies on gut microbiota composition.It visually demonstrates the contrasting changes in important bacteria, providing a quick reference for understanding which therapies promote beneficial bacteria and which reduce harmful bacteria.As it can be seen in Figure 5, FMT and various treatments (including mesalamine, corticosteroids, and immunosuppressants) resulted in a greater increase in beneficial bacteria, indicating their positive impact on gut microbiota composition.
Table 4 shows the comparison of beneficial and harmful bacteria in IBD patients highlights significant differences in the microbial composition associated with disease progression.Notably, beneficial bacteria such as Faecalibacterium prausnitzii, Roseburia, and Bifidobacterium are frequently linked with anti-inflammatory effects and the production of SCFAs, which are crucial for maintaining gut health.Studies such as those by Vich Vila et al. [37] and Sokol et al. [40] emphasize the increase in these beneficial bacteria in response to treatments such as anti-TNF therapy and FMT, indicating their role in promoting remission in IBD patients.Conversely, the table also identifies several harmful bacteria associated with IBD, such as Bacteroides, Ruminococcus gnavus, and Escherichia coli.Their presence is frequently associated with an imbalance in microbiome inflammation, as indicated in research conducted by Ananthakrishnan et al. [38] and Franzosa et al. [39].For example, Ruminococcus gnavus is linked to inflammatory complexes that can exacerbate IBD.Furthermore, the excessive presence of Escherichia coli and Clostridioides difficile is linked to intestinal infections and exacerbated illness outcomes.Moreover, Lachnospiraceae and Ruminococcaceae can be both helpful or harmful, depending on the circumstances.The dual roles of these bacteria are highlighted in recent studies by Ribaldone et al. [43] and Rausch et al. [53].
Ribaldone et al. [43] demonstrated that adalimumab therapy in CD patients led to a significant increase in Firmicutes and Bacteroidetes and a decrease in Actinobacteria and Proteobacteria.This shift in microbial composition is associated with improved clinical outcomes.Similarly, Rausch et al. [53] found that anti-inflammatory treatments in IBD patients increased the abundance of beneficial bacteria such as Faecalibacterium prausnitzii, Roseburia, and Bifidobacterium, while harmful bacteria such as Escherichia coli and Clostridioides difficile decreased, further supporting the literature [70,71] on the importance of microbiota modulation in managing IBD.

Importance of Analyzing the Microbiome in IBD
According to "World Gastroenterology Organization Global Guidelines" on probiotics and prebiotics from February 2023 [72], studies on the use of probiotics in CD have shown no significant benefits for inducing or maintaining remission of the condition.These findings suggest that probiotics are not effective in the long-term management of the disease.In line with these conclusions, Sokol et al. [40] focused on FMT rather than probiotics, leading to the conclusion that FMT helps maintain remission and positively alters gut microbiota composition in CD patients.
Despite the popularity of probiotics for various digestive issues, the current evidence does not support their use as an effective treatment for inducing or maintaining remission in Crohn's disease [73].
On the other hand, the same report highlighted some promising findings regarding the use of probiotics in the treatment of UC [72].Individual studies included in "World Gastroenterology Organization Global Guidelines" indicated that certain probiotics might be safe and potentially as effective as conventional therapies in achieving response and remission rates for patients with mild to moderately active UC; this finding was applicable to both adults and pediatric populations.These findings suggest a potential role for probiotics as an alternative treatment option in specific cases of ulcerative colitis.This study also reflects these promising findings.Thus, the experimental research by Huang et al. [41] on the use of probiotics for treating UC led to the conclusion that various probiotic strains modulate gut microbiota, reduce inflammation, and improve intestinal barrier function.
However, it is important to consider the broader context of these findings.According to a meta-analysis conducted by Kaur et al. [74], the efficacy of probiotics for inducing remission in mild to moderate UC is not sufficient.Many studies reviewed in this analysis, such as those by Vich Vila et al. [37] and Ananthakrishnan et al. [38], show positive correlations between gut microbiota composition and treatment outcomes but also note the need for more rigorous, long-term studies to validate these findings.

Discussions
The intricate link between gut microbiota and IBD has received significant attention, especially in terms of understanding the distinct responses to various treatments.
Vich Vila et al. [37] investigated the composition of the microbiome in IBD patients undergoing anti-TNF therapy.Their investigation revealed an increase in good bacteria, such as Faecalibacterium prausnitzii and Roseburia, among responders.These findings align with previous studies.For example, Franzosa et al. [39] similarly observed elevated levels of Roseburia and Ruminococcaceae after administering ustekinumab.These taxonomic groups have been extensively studied for their ability to reduce inflammation and produce butyrate, crucial for maintaining a healthy gut [75,76].
Ananthakrishnan et al. [38] highlighted the role of the gut microbiome in predicting responses to vedolizumab, noting increased Streptococcus salivarium in responders.This aligns with Costello et al. [42], who observed an increase in beneficial bacteria such as Anaerofilum pentosovorans and Ruminococcaceae post-FMT, suggesting that successful therapy is often marked by a rise in beneficial butyrate-producing bacteria.These bacteria help maintain the integrity of the intestinal barrier and possess anti-inflammatory properties [77].Mayorga et al. [78] found a correlation between gut microbiota diversity and IBD severity, with reduced diversity linked to more severe disease.Sokol et al. [40] demonstrated that FMT significantly altered the gut microbiota composition in CD patients, increasing the prevalence of Roseburia and Faecalibacterium prausnitzii.These results align with findings by Huang et al. [41], who reviewed the effects of various probiotics in UC, highlighting strains such as Lactobacillus reuteri and Bifidobacterium longum for their beneficial impact on gut microbiota and inflammation reduction.Li et al. [79] also found that probiotics significantly improve clinical symptoms in IBD patients, further supporting their beneficial role.
Conversely, several studies identified harmful bacteria associated with IBD activity.Vich Vila et al. [37] noted higher levels of Bacteroides and Ruminococcus gnavus in nonresponders to anti-TNF therapy.He et al. [44] found increased Proteobacteria and Escherichia-Shigella in UC patients, linked to heightened inflammation and gut barrier disruption.These bacteria's pro-inflammatory roles are well documented, with Proteobacteria often acting as pathobionts that exacerbate IBD symptoms [80].Gilliland et al. [81] also noted that the presence of these bacteria is linked to higher illness severity in patients with IBD.
Nikolaus et al. [51] highlighted the association between increased tryptophan metabolism and IBD activity, finding higher levels of Escherichia coli and Clostridioides difficile in active disease phases.In line with these findings, Khorsand et al. [82] revealed that individuals with active CD and UC had raised levels of Enterobacteriaceae and Fusobacteriaceae, providing more evidence of their detrimental effects.
Fornelos et al. [52] examined the effects of N-acylethanolamines on gut bacteria, discovering that these substances have varying effects on bacterial proliferation in individuals with IBD.They noted a rise in pathogenic bacteria, specifically Escherichia coli and Bacteroides vulgatus, suggesting that changes in gut metabolic conditions can impact disease development.Coufal et al. [48] corroborated these findings, observing comparable microbial alterations in IBD.Nieva et al. [83] demonstrated that targeted dietary interventions to manipulate gut microbiota can effectively regulate disease activity in patients with IBD.
A study conducted by Pittayanon et al. [49] showed an increase in bad bacteria, specifically Proteobacteria and Fusobacteria.This agrees with other studies in the literature, as Sorboni et al. [84] highlighted the significance of microbiota regulation in the management of IBD, identifying the presence of the same harmful bacteria.Furthermore, Vujkovic-Cvijin et al. [85] observed a similar dysbiosis as a characteristic feature of IBD.
The comparative analysis of these studies highlights the dual role of specific bacterial taxa in IBD, with beneficial bacteria often promoting anti-inflammatory effects and maintaining gut health while harmful bacteria exacerbate inflammation and disrupt gut barrier function.This duality is crucial for understanding therapeutic outcomes and developing targeted interventions [86].Restoring a balanced gut microbiota through therapies such as probiotics, FMT, and microbial-targeted treatments holds promise for managing IBD more effectively.
Future research should prioritize large-scale, long-term studies with standardized methodologies to validate these findings and elucidate the mechanisms through which gut microbiota modulate IBD.

Limitations
Many of the studies reviewed had relatively small sample sizes and limited diversity in the participant populations.For instance, Vich Vila et al. [37] included 150 participants with diverse ethnic backgrounds, but the majority had moderate disease, which may not fully represent the broader IBD patient population.Similarly, other studies, such as those by Ribaldone et al. [53] and Crothers et al. [45], included only 12 participants, limiting the generalizability of the findings.
The reviewed studies employed different methodologies, including observational studies, randomized controlled trials, and systematic reviews.This variability can introduce heterogeneity in the results, making direct comparisons challenging.For example, Sokol et al. [40] conducted a randomized controlled study on FMT, while Huang et al. [41] reviewed experimental research on probiotics, which can lead to differences in outcome measures and interpretations.
The studies reviewed used various therapeutic interventions such as anti-TNF therapy, vedolizumab, ustekinumab, probiotics, and FMT.These interventions have different mechanisms of action and may affect the gut microbiota in distinct ways, complicating the comparison of their effects on bacterial composition.For example, Ananthakrishnan et al. [38] focused on vedolizumab, whereas Costello et al. [42] investigated the effects of FMT, highlighting the need for caution when generalizing findings across different treatments.
Several studies focused on particular bacterial groups, possibly neglecting other crucial components of the gut microbiota that could have major impacts on IBD.For example, while studies frequently highlighted Faecalibacterium prausnitzii and Roseburia as beneficial, less attention was devoted to other beneficial bacteria that might also contribute to disease modulation.This selective focus can lead to an incomplete understanding of the microbiome's overall impact on IBD.
Several studies had relatively short follow-up periods, limiting the ability to assess the long-term effects of the interventions on gut microbiota and clinical outcomes.For instance, Costello et al. [42] evaluated the effects of FMT on 8-week remission, but longer-term data are needed to determine the sustainability of these changes.
There is a potential for publication bias, as studies with positive results are more likely to be published than those with negative or inconclusive findings.This bias can skew the overall understanding of the role of gut microbiota in IBD and the effectiveness of microbiome-targeted therapies.

Conclusions
This comprehensive study features the significant role of gut microbiota in the onset and management of IBD.Numerous studies have pinpointed key bacteria, including Faecalibacterium prausnitzii and Roseburia, which are vital for maintaining gut health and improving IBD symptoms.
Conversely, detrimental bacteria, including Escherichia coli and Clostridioides difficile, were often linked to exacerbated clinical results.Therapies such as anti-TNF, vedolizumab, and fecal microbiota transplantation have shown promise in favorably altering the gut microbiota composition, enhancing treatment efficacy and patient prognosis.
Future research should prioritize large-scale, long-term studies with standardized methodologies to validate these findings and elucidate the mechanisms through which gut microbiota modulate IBD.Addressing these research gaps will be crucial for advancing microbiome-based therapeutic strategies and improving patient outcomes in IBD.Ultimately, the composition and predictability of gut microbiota have an intricate and multidimensional role in the effectiveness of treating IBD.Future studies should also focus on longitudinal analyses using advanced sequencing techniques to uncover potential biomarkers.In conclusion, a more profound comprehension of the interaction between gut microbiota and treatments for IBD has the potential to lead to groundbreaking therapeutic approaches that specifically focus on the microbiome.

Figure 1 26 Figure 1 .
Figure 1 presents the PRISMA flow diagram, which is essential for detailing the selection process of the studies included in this review.This diagram visually represents the identification, screening, eligibility, and inclusion phases of this systematic review process.The relevance of Figure 1 lies in its ability to provide a transparent methodology explaining how the final set of studies was determined.Int.J. Mol.Sci.2024, 25, x FOR PEER REVIEW 5 of 26

Figure 1 .
Figure 1.PRISMA framework.Reason 1 *: The study does not utilize the appropriate design for the review.Reason 2 **: The study does not meet the minimum quality threshold based on the assessment criteria.Reason 3 ***: The study lacks necessary data for extraction and analysis.Reason 4 ****: The study's follow-up period was too short to assess the long-term outcomes.Reason 5 ****: The study is a review, commentary, or editorial rather than original research.Reason 6 ****: Full text is not available.2.8.Statistical Analysis Key studies from this systematic research include those of Vich Vila et al. (2018) [37], which assessed gut microbiota composition in IBD patients treated with anti-TNF therapy, and Ananthakrishnan et al. (2017) [38], which explored gut microbiota as a predictor of response to vedolizumab in IBD patients.Franzosa et al. (2019) [39] studied the effects of ustekinumab on gut microbiota, while Sokol et al. (2020) [40] evaluated FMT to maintain remission in CD patients.Huang et al. (2023) [41] reviewed the use of probiotics for treating UC, and Costello et al. (2019) [42] evaluated FMT as a treatment strategy for this disease.Ribaldone et al. (2019) [43] examined microbiome changes within 6 months of adalimumab therapy in CD patients, while He et al. (2021) [44] correlated clinical aspects with microbiome composition in UC patients.

Figure 2 ,
below, illustrates the sensitivity analysis conducted to determine the effect of removing each individual study on the pooled effect size.Int.J. Mol.Sci.2024, 25, x FOR PEER REVIEW 10 of 26

Figure 3 .
Figure 3. Risk bias analysis of the 17 studies.
Int. J. Mol.Sci.2024, 25, x FOR PEER REVIEW 14 of 26 pathogenic bacteria, including Escherichia coli, Clostridioides difficile, and other Proteobacteria, are regularly decreased after successful treatments [40,44].Ribaldone et al. [43] also observed a decrease in Proteobacteria in CD patients treated with adalimumab, indicating a positive shift towards a healthier gut microbiota composition.Similarly, Rausch et al.

Figure 5 .
Figure 5.The number of key bacteria that increased (green) and decreased (red) for each therapy.Figure 5.The number of key bacteria that increased (green) and decreased (red) for each therapy.

Figure 5 .
Figure 5.The number of key bacteria that increased (green) and decreased (red) for each therapy.Figure 5.The number of key bacteria that increased (green) and decreased (red) for each therapy.

Table 1 .
Overview of study characteristics and main conclusions in gut microbiota and IBD treatment research.

Table 2 .
Abundance of bacteria in IBD patients as compared to healthy controls.

Table 2 .
Abundance of bacteria in IBD patients as compared to healthy controls.

Table 3 .
Comparison table for therapies and microbiota changes in CD and UC.

Table 4 .
Classification of bacteria as either beneficial or harmful with a brief explanation of their roles.